1882-71-9Relevant articles and documents
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Bergmann,Bentov
, p. 1654 (1955)
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A synthetic resveratrol analog termed Q205 reactivates latent HIV-1 through activation of P-TEFb
Duan, Heng,Li, Chao,Li, Lin,Li, Yibin,Liang, Taizhen,Liu, Shuwen,Qiao, Xinman,Wu, Ziyao,Xi, Baomin,Zhang, Xuanxuan,Zhao, Kangni
, (2022/01/19)
The persistence of HIV-1 latent reservoir creates the major obstacle toward an HIV-1 cure. The “shock and kill” strategy aims to reverse HIV-1 proviral latency using latency-reversing agents (LRAs), thus boosting immune recognition and clearance to residual infected cells. Unfortunately, to date, none of these tested LRA candidates has been demonstrated effectiveness and/or safety in reactivation HIV-1 latency. The discovery and development of effective, safe and affordable LRA candidates are urgently needed for creating an HIV-1 functional cure. Here, we designed and synthesized a series of small-molecule phenoxyacetic acid derivatives based on the resveratrol scaffold and found one of them, named 5, 7-dimethoxy-2-(5-(methoxymethyl) furan-2-yl) quinazolin-4(3H)-one (Q205), effectively reactivated latent HIV-1 in latent HIV-1-infected cells without a corresponding increase in induction of potentially damaging cytokines. The molecular mechanism of Q205 is shown to increase the phosphorylation of the CDK9 T-loop at position Thr186, dissociate positive transcription elongation factor b (P-TEFb) from BRD4, and promote the Tat-mediated HIV-1 transcription and RNA polymerase II (RNAPII) C-terminal domain (CTD) on Ser (CTD-Ser2P) to bind to the HIV-1 promoter. This study provides a unique insight into resveratrol modified derivatives as promising leads for preclinical LRAs, which in turn may help toward inhibitor design and chemical optimization for improving HIV-1 shock-and kill-based efforts.
Scaffold hopping and optimisation of 3’,4’-dihydroxyphenyl- containing thienopyrimidinones: synthesis of quinazolinone derivatives as novel allosteric inhibitors of HIV-1 reverse transcriptase-associated ribonuclease H
Tocco, Graziella,Esposito, Francesca,Caboni, Pierluigi,Laus, Antonio,Beutler, John A.,Wilson, Jennifer A.,Corona, Angela,Le Grice, Stuart F. J.,Tramontano, Enzo
, p. 1953 - 1963 (2020/11/09)
Bioisosteric replacement and scaffold hopping are powerful strategies in drug design useful for rationally modifying a hit compound towards novel lead therapeutic agents. Recently, we reported a series of thienopyrimidinones that compromise dynamics at the p66/p51 HIV-1 reverse transcriptase (RT)-associated Ribonuclease H (RNase H) dimer interface, thereby allosterically interrupting catalysis by altering the active site geometry. Although they exhibited good submicromolar activity, the isosteric replacement of the thiophene ring, a potential toxicophore, is warranted. Thus, in this article, the most active 2-(3,4-dihydroxyphenyl)-5,6-dimethylthieno[2,3-d]pyrimidin-4(3H)-one 1 was selected as the hit scaffold and several isosteric substitutions of the thiophene ring were performed. A novel series of highly active RNase H allosteric quinazolinone inhibitors was thus obtained. To determine their target selectivity, they were tested against RT-associated RNA-dependent DNA polymerase (RDDP) and integrase (IN). Interestingly, none of the compounds were particularly active on (RDDP) but many displayed micromolar to submicromolar activity against IN.
Fluorescent biaryl uracils with C5-dihydro- And quinazolinone heterocyclic appendages in PNA
Heidari, Ali,Ghorbani-Choghamarani, Arash,Hajjami, Maryam,Hudson, Robert H.E.
, (2020/04/29)
There has been much effort to exploit fluorescence techniques in the detection of nucleic acids. Canonical nucleic acids are essentially nonfluorescent; however, the modification of the nucleobase has proved to be a fruitful way to engender fluorescence. Much of the chemistry used to prepare modified nucleobases relies on expensive transition metal catalysts. In this work, we describe the synthesis of biaryl quinazolinone-uracil nucleobase analogs prepared by the condensation of anthranilamide derivatives and 5-formyluracil using inexpensive copper salts. A selection of modified nucleobases were prepared, and the effect of methoxy- or nitro- group substitution on the photophysical properties was examined. Both the dihydroquinazolinone and quinazolinone modified uracils have much larger molar absorptivity (~4-8×) than natural uracil and produce modest blue fluorescence. The quinazolinone-modified uracils display higher quantum yields than the corresponding dihydroquinazolinones and also show temperature and viscosity dependent emission consistent with molecular rotor behavior. Peptide nucleic acid (PNA) monomers possessing quinazolinone modified uracils were prepared and incorporated into oligomers. In the sequence context examined, the nitro-substituted, methoxy-substituted and unmodified quinazolinone inserts resulted in a stabilization (?Tm = +4.0/insert; +2.0/insert; +1.0/insert, respectively) relative to control PNA sequence upon hybridization to complementary DNA. All three derivatives responded to hybridization by the “turn-on” of fluorescence intensity by ca. 3-to-4 fold and may find use as probes for complementary DNA sequences.
